This proposal describes a four-year program for the establishment of an independent research career dedicated to investigating the actions and mechanisms of anesthesia at the level of neural systems in humans. The career development plan emphasizes mentored training in functional magnetic resonance imaging (fMRI), and a sequence of both imaging and non-imaging studies focused on fear learning and memory systems. The Candidate: Kane O. Pryor, MD is an Assistant Professor in Anesthesiology at Weill Medical College of Cornell University (WMCCU), and at Memorial Sloan-Kettering Cancer Center (MSKCC). His immediate career goal is to acquire a high level of expertise in fMRI, statistical and mathematical techniques through training and research with the Functional Neuroimaging Laboratory (FNL) at WMCCU. His longer term goal is an independent research program dedicated to translating molecular knowledge about anesthetic actions into human studies on neural systems and clinical interventions. He is especially interested in investigating whether anesthetic drugs have a role in the prevention and treatment of certain psychiatric disorders. Research Environment: Dr. Pryor will be mentored by David A. Silbersweig, MD, Professor of Neurology and Neuroscience and Psychiatry, and Co-Director of the FNL. Dr. Silbersweig is an expert in fMRI and the neurobiology of fear. Training in fMRI will occur in a research and didactic program based at the FNL, and modeled on Dr. Silbersweig's NIH R25 training program. Imaging studies will be conducted at the Citigroup Biomedical Imaging Center (CBIC), a research-dedicated imaging facility. Non-imaging studies will be conducted at the WMCCU NIH M01 General Clinical Research Center. Research Plan: Dr. Pryor's research will focus on unconscious, amygdala-dependent fear learning and memory systems. The effects of several anesthetic drugs on these systems will be evaluated by conducting experiments while subjects are receiving controlled infusions of the drugs at sedative doses. The actions of the drugs will first be characterized in a non-imaging study, incorporating behavioral and physiological measures. The neural activation patterns associated with these effects will then be evaluated by duplicating the experiments in an fMRI study. Three specific aims will be addressed: To determine the effect of anesthetic drugs on (I) the acquisition and early extinction ofPavlovian fear conditioning and (II) unconscious processing of fearful stimuli;and (III) to determine the neuroanatomical correlates for these effects. RELEVANCE. The neural systems studied in these experiments are also involved in several psychiatric disorders. Anesthetic drugs that inadequately suppress these systems may permit the stress response to surgery to potentiate the development of postoperative psychiatric morbidity. Conversely, anesthetic drugs that profoundly suppress these systems could develop a preventative or therapeutic role in certain patients.